Abstract
Tumor cell proliferation, survival and migration are regulated by the deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), a tumor suppressor that serves as a scaffold protein for H-Ras and TRAF2. Importantly, the oncogenic histone methyl-transferase EZH2 epigenetically down-regulates DAB2IP in a variety of tumors. Recently, we demonstrated that DAB2IP is negatively regulated by Akt-dependent phosphorylation and SCFFbw7-mediated degradation. Here, we further identify the oncoprotein Smurf1, an E3-ubiquitin ligase, as a novel negative regulator of DAB2IP. Smurf1-mediated cellular proliferation and migration are largely dependent on the presence of DAB2IP, suggesting that DAB2IP is a key effector molecule of Smurf1 oncogenic function. Additionally, we identify that similar to DAB2IP, Smurf1 is also a target of phosphorylation by both Akt1 and Akt2 kinases, which enhances Smurf1 abundance, leading to a reduction in DAB2IP. Given the role of DAB2IP in tumorigenesis and metastasis, our data identify Smurf1 as an upstream oncogenic factor that negatively regulates DAB2IP to govern aberrant cell growth and migration.
Highlights
Tumor metastasis is a major obstacle to curing cancer and is a driving mechanism to increased mortality in cancer patients [1]
We have elucidated a novel mechanism controlling DAB2IP stability mediated by the Akt/Smurf1 oncogenic signaling pathway
Our results indicate that DAB2IP interacts with Smurf1 and Smurf2 of the Nedd4-like E3 ligase family, and that Smurf1 is largely responsible for degradation of DAB2IP through ubiquitination-mediated proteolysis
Summary
Tumor metastasis is a major obstacle to curing cancer and is a driving mechanism to increased mortality in cancer patients [1]. While the molecular mechanisms remain poorly defined, overexpression of specific oncoproteins [3] or downregulation of specific tumor suppressor proteins [4] have been shown to play important roles in tumor growth and metastasis. To this end, deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), is a tumor suppressor in various types of human cancer [5,6,7,8,9] where loss of DAB2IP expression is associated with poor prognosis and increased tumor metastasis [6, 8,9,10,11]. DAB2IP is involved in TNFα-induced apoptosis in prostate cancer cells in part by suppressing the ASK1-JNK and PI3K-AKT pathway [11], and in endothelial cells via inhibiting the ASK1-JNK pathway [17]
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